莲子与姜辣素组合物抗癌及止吐减毒增效作用研究
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摘要
背景呕吐是临床多种疾病的常见症状,可引起水电解质紊乱。化疗药物毒副作用最痛苦的症状之一即是呕吐,而传统抗呕吐药对癌症放化疗后呕吐的治疗疗效差,且常需联合用药。化学制剂止吐药5-羟色胺3受体拮抗剂和神经激肽1(NK1)受体拮抗剂等适于放化疗后的呕吐治疗,但仍存在作用靶点单一、不良反应大的问题。因此,寻找天然、低毒、广谱的止吐药物成为亟待解决的问题。目的研究莲子与姜辣素组合物(莲姜组合物)的抗癌及对化疗呕吐的抑制作用。方法研究时间为2017年。选取昆明种SPF级雄性小鼠96只、健康成年黑色CL级雄性水貂72只为实验动物。在每只小鼠右腋窝皮下接种0.2 ml(含瘤细胞2×106个)瘤细胞悬液(S180肉瘤、艾氏腹水瘤)。接种次日将小鼠随机分4组,每组12只。正常对照组给予蒸馏水0.5 ml灌胃;环磷酰胺组给予环磷酰胺20 g/kg腹腔注射;姜辣素组给予姜辣素10 g/kg(相当于含生药量)灌胃;莲姜组合物组给予莲姜组合物10 g/kg(相当于含生药量)灌胃;连续给药10 d。比较各组小鼠肿瘤质量,并计算相应的肿瘤抑制率。同时期,将72只水貂随机分为3组,分别用于研究莲姜组合物对顺铂(顺铂呕吐组)、阿扑吗啡(阿扑吗啡呕吐组)、硫酸铜(硫酸铜呕吐组)3种药物引起的呕吐的影响,每组24只;再将顺铂呕吐组水貂随机分为正常对照、阳性对照、姜辣素、莲姜组合物亚组,即正常对照亚组1、阳性对照亚组1、姜辣素亚组1、莲姜组合物亚组1,每组6只;阿扑吗啡呕吐组、硫酸铜呕吐组的亚组分组同上,每个亚组6只。顺铂呕吐组中,正常对照亚组1给予5 ml 0.9%氯化钠溶液灌胃;阳性对照亚组1给予盐酸昂丹司琼注射液2 mg/kg腹腔注射;姜辣素亚组1给予姜辣素10 g/kg(相当于含生药量)灌胃;莲姜组合物亚组1给予莲姜组合物10 g/kg(相当于含生药量)灌胃;除空白对照组外,其余水貂在预处理30 min后给予顺铂腹腔注射。阿扑吗啡呕吐组、硫酸铜呕吐组的各亚组给药方法同上,除空白对照组外,其余水貂在预处理30 min后分别给予相应的阿扑吗啡、硫酸铜腹腔注射。6 h后记录并比较顺铂呕吐组、阿扑吗啡呕吐组、硫酸铜呕吐组的各亚组水貂呕吐发生率、呕吐潜伏期、干呕次数、呕吐次数。结果环磷酰胺组、姜辣素组、莲姜组合物组小鼠S180肉瘤、艾氏腹水瘤肿瘤质量轻于正常对照组(P<0.05)。环磷酰胺组、姜辣素组、莲姜组合物组小鼠S180肉瘤、艾氏腹水瘤肿瘤抑制率分别为65.5%、31.9%、53.4%及64.7%、26.7%、54.5%。顺铂呕吐组中,阳性对照亚组1、姜辣素亚组1、莲姜组合物亚组1水貂呕吐潜伏期长于正常对照亚组1,干呕次数、呕吐次数少于正常对照亚组1(P<0.05)。阿扑吗啡呕吐组中,阳性对照亚组2、姜辣素亚组2、莲姜组合物亚组2水貂呕吐潜伏期长于正常对照亚组2,干呕次数、呕吐次数少于正常对照亚组2(P<0.05)。硫酸铜呕吐组中,阳性对照亚组3、姜辣素亚组3、莲姜组合物亚组3水貂呕吐潜伏期长于正常对照亚组3,干呕次数、呕吐次数少于正常对照亚组3(P<0.05)。结论莲姜组合物可抑制小鼠S180肉瘤、艾氏腹水瘤,抑制顺铂、阿扑吗啡、硫酸铜所致呕吐,有抗癌、止吐减毒增效作用。
Background Vomiting is the most commonly experienced symptom of various diseases in the clinic which can cause water and electrolyte disorders.It is also the most commonly experienced side effects in patients receiving chemotherapy.For managing vomiting induced by chemotherapy and radiotherapy,traditional anti-vomiting treatments have poor efficacies,and combination therapies are often needed.Although chemical preparations such as 5-HT3 receptor antagonist and neurokinin 1(NK1) receptor antagonists are suitable for managing vomiting,their scopes of action are too narrow,and adverse reactions are often severe.Thus,the development of natural,low-toxic,broad-spectrum antiemetic drugs is urgently required. ObjectiveTo study the anticancer and anti-emesis efficacy of semen nelumbinis and gingerol composition(lotus-ginger composition).Methods This study was conducted in 2017.Ninty-six SPF male Kunming mice and 72 healthy CL black adult male minks were selected.Each mouse was inoculated subcutaneously 0.2 ml(containing 2×106 tumor cells) tumorigenic cell suspension(S180 sarcoma,EAC) in the right axilla.The day after inoculation,the mice were randomly and equally divided into the blank control group,cyclophosphamide group,ginerol group and lotus-ginger composition group,receiving intragastric administration of distilled water 0.5 ml,intraperitoneal injection of cyclophosphamide(20 g/kg),intragastric administration of gingerol(10 g/kg,equivalent to crude drug dosage),intragastric administration of lotus-ginger composition(10 g/kg,equivalent to crude drug dosage),respectively,for consecutive 10 days.The tumor mass of mice in each group was compared,and the inhibition rates of tumor were also calculated.Meanwhile,the minks were randomly and equally divided into cisplatin,apomorphine and copper sulphate induced vomiting groups.Cisplatin induced vomiting group was equally divided into four subgroups,the blank control,positive control,gingerol,and lotus-ginger composition subgroups,treated with intragastric administration of 0.9% sodium chloride solution(5 ml),intraperitoneal injection of ondansetron(2 mg/kg),intragastric administration of gingerol(10 g/kg,equivalent to crude drug dosage),intragastric administration of lotus-ginger composition(10 g/kg,equivalent to crude drug dosage),respectively.Cisplatin was administered 30 minutes after treatment with the antiemetic agent or its vehicle,except for the blank control subgroup.The same experimental procedure was performed on apomorphine and copper sulphate induced vomiting groups,receptively,except that apomorphine and copper sulphate were administered to the corresponding subgroups(blank control subgroup was not included) at 30 minutes after treatment with the antiemetic agent or its vehicle.Subgroups of cisplatin,apomorphine and copper sulphate induced vomiting groups were observed the emetic responses and the latency,the number of both retching and vomiting at 6 hours following the administration of cisplatin,apomorphine,copper sulphate,respectively.Results Compared with the blank control group,the tumor of S180 sarcoma and EAC was lighter in cyclophosphamide group,gingerol group and lotus-ginger composition group(P<0.05).The inhibition rate of S180 sarcoma in cyclophosphamide group,gingerol group and lotus-ginger composition group was 65.5%,31.9%,and 53.4%,respectively.The inhibition rate of EAC was 64.7%,26.7%,and 54.5%,respectively.Cisplatin evoked emetic response in minks,pretreatment with ondansetron,gingerol,lotus-ginger composition prolonged the latency,reduced the number of retches and vomits induced by cisplatin(P<0.05).Apomorphine also evoked emetic response in minks,pretreatment with ondansetron,gingerol,lotus-ginger composition prolonged the latency,reduced the number of retches and vomits induced by apomorphine(P<0.05).Copper sulphate evoked emetic response in minks,too,pretreatment with ondansetron,gingerol,lotus ginger composition prolonged the latency,reduced the number of retches and vomits induced by apomorphine(P<0.05).Conclusion The composition can inhibit S180 sarcoma and EAC tumor in mice,it also can inhibit vomitings induced by cisplatin,apomorphine and copper sulphate,and have synergistic effect and toxicity attenuation in the treatment of cancer.
Background Vomiting is the most commonly experienced symptom of various diseases in the clinic which can cause water and electrolyte disorders.It is also the most commonly experienced side effects in patients receiving chemotherapy.For managing vomiting induced by chemotherapy and radiotherapy,traditional anti-vomiting treatments have poor efficacies,and combination therapies are often needed.Although chemical preparations such as 5-HT3 receptor antagonist and neurokinin 1(NK1) receptor antagonists are suitable for managing vomiting,their scopes of action are too narrow,and adverse reactions are often severe.Thus,the development of natural,low-toxic,broad-spectrum antiemetic drugs is urgently required. ObjectiveTo study the anticancer and anti-emesis efficacy of semen nelumbinis and gingerol composition(lotus-ginger composition).Methods This study was conducted in 2017.Ninty-six SPF male Kunming mice and 72 healthy CL black adult male minks were selected.Each mouse was inoculated subcutaneously 0.2 ml(containing 2×106 tumor cells) tumorigenic cell suspension(S180 sarcoma,EAC) in the right axilla.The day after inoculation,the mice were randomly and equally divided into the blank control group,cyclophosphamide group,ginerol group and lotus-ginger composition group,receiving intragastric administration of distilled water 0.5 ml,intraperitoneal injection of cyclophosphamide(20 g/kg),intragastric administration of gingerol(10 g/kg,equivalent to crude drug dosage),intragastric administration of lotus-ginger composition(10 g/kg,equivalent to crude drug dosage),respectively,for consecutive 10 days.The tumor mass of mice in each group was compared,and the inhibition rates of tumor were also calculated.Meanwhile,the minks were randomly and equally divided into cisplatin,apomorphine and copper sulphate induced vomiting groups.Cisplatin induced vomiting group was equally divided into four subgroups,the blank control,positive control,gingerol,and lotus-ginger composition subgroups,treated with intragastric administration of 0.9% sodium chloride solution(5 ml),intraperitoneal injection of ondansetron(2 mg/kg),intragastric administration of gingerol(10 g/kg,equivalent to crude drug dosage),intragastric administration of lotus-ginger composition(10 g/kg,equivalent to crude drug dosage),respectively.Cisplatin was administered 30 minutes after treatment with the antiemetic agent or its vehicle,except for the blank control subgroup.The same experimental procedure was performed on apomorphine and copper sulphate induced vomiting groups,receptively,except that apomorphine and copper sulphate were administered to the corresponding subgroups(blank control subgroup was not included) at 30 minutes after treatment with the antiemetic agent or its vehicle.Subgroups of cisplatin,apomorphine and copper sulphate induced vomiting groups were observed the emetic responses and the latency,the number of both retching and vomiting at 6 hours following the administration of cisplatin,apomorphine,copper sulphate,respectively.Results Compared with the blank control group,the tumor of S180 sarcoma and EAC was lighter in cyclophosphamide group,gingerol group and lotus-ginger composition group(P<0.05).The inhibition rate of S180 sarcoma in cyclophosphamide group,gingerol group and lotus-ginger composition group was 65.5%,31.9%,and 53.4%,respectively.The inhibition rate of EAC was 64.7%,26.7%,and 54.5%,respectively.Cisplatin evoked emetic response in minks,pretreatment with ondansetron,gingerol,lotus-ginger composition prolonged the latency,reduced the number of retches and vomits induced by cisplatin(P<0.05).Apomorphine also evoked emetic response in minks,pretreatment with ondansetron,gingerol,lotus-ginger composition prolonged the latency,reduced the number of retches and vomits induced by apomorphine(P<0.05).Copper sulphate evoked emetic response in minks,too,pretreatment with ondansetron,gingerol,lotus ginger composition prolonged the latency,reduced the number of retches and vomits induced by apomorphine(P<0.05).Conclusion The composition can inhibit S180 sarcoma and EAC tumor in mice,it also can inhibit vomitings induced by cisplatin,apomorphine and copper sulphate,and have synergistic effect and toxicity attenuation in the treatment of cancer.
引文
[1] CHEN D M, ZHAO J, CONG W H.Chinese herbal medicines facilitate the control of chemotherapy-induced side effects in colorectal cancer:progress and perspective[J]. Front Pharmacol, 2018, 9:1442. DOI:10.3389/fphar.2018.01442.
[2] GRUNBERG S, CHUA D, MARU A, et al. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy:randomized, doubleblind study protocol——EASE[J]. J Clin Oncol, 2011, 29(11):1495-1501. DOI:10.1200/JCO.2010.31.7859.
[3]李琳.草酸铈与姜辣素止呕及抗癌增效作用研究[D].青岛:青岛大学,2013.LI L.Cerium oxalate and gingerol anti-nausea effect and anti-tumor effect research[D]. Qingdao:Qingdao University, 2013.
[4]冯霞,易若琨,孙鹏,等.巴莲莲子生物碱提取物对人肝癌细胞HepG2的体外抗癌效果[J].食品科学,2017, 38(19):206-211. DOI:10.7506/spkx1002-6630-201719033.FENG X, YI R K, SUN P, et al. In vitro anticancer activity of alkaloids extracted from ha lotus seeds against human hepatoma HepG2 cells[J]. Food Science, 2017, 38(19):206-211.DOI:10.7506/spkx 1002-6630-201719033.
[5]邵亨元.平安饮治疗妊娠呕吐症[J].新中医,1995, 27(11):37. DOI:10.13457/j.cnki.jncm.1995.11.023.SHAO H Y.Pingan drink for pregnancy and vomiting[J]. NewJournal of Traditional Chinese Medicine, 1995, 27(11):37.DOI:10.13457/j.cnki.jncm. 1995.11.023.
[6]任爱玲,李晓玲,侯宁,等.楷木提取物对小鼠肿瘤的抑制作用[J].徐州医学院学报,2015, 35(10):660-662.
[7]张继国,杨杰,刘占涛,等.一种莲子天然药物组合物及制备方法和抗呕吐用途:CN104138419A[P]. 2014-11-12.
[8]岳旺,张芳,王蕾,等.一种新型呕吐动物模型——水貂[J].药学学报,2003,38(2):89-91. DOI:10.3321/j.issn:0513-4870.2003.02.003.YUE W, ZHANG F, WANG L, et al. A new vomiting animal model-mink[J]. Acta Pharmaceutica Sinica, 2003, 38(2):89-91. DOI:10.3321/j.issn:0513-4870.2003.02.003.
[9]王玉霞,郭兴科,李圆圆,等.高良姜与生姜组合物的抗肿瘤止呕作用[J].泰山医学院学报,2016, 37(7):735-737.DOI:10.3969/j.issn. 1004-7115.2016.07.005.WANG Y X, GUO X K, LI Y Y, et al. The antitumor and antiemetic effect of zingiber and rhizoma composite[J].Journal of Taishan Medical College, 2016, 37(7):735-737. DOI:10.3969/j.issn. 1004-7115.2016.07.005.
[10]杨鹰,王爱民,石振艳,等.紫苏叶与生姜组合物在癌症放、化疗中止吐增效作用[J].中华中医药学刊,2015, 33(2):355-357. DOI:10.13193/j.issn.1673-7717.2015.02.032.YANG Y, WANG A M, SHI Z Y, et al. Detoxification and synergistic effect of zingiber-rhizoma compositionin radiotherapy and chemotherapy[J]. Chinese Archives of Traditional Chinese Medicine, 2015, 33(2):355-357. DOI:10.13193/j.issn. 1673-7717.2015.02.032.
[11] QIAN Q H, YUE W, WANG Y X, et al. Gingerol inhibits cisplatin-induced vomiting by down regulating5-hydroxytryptamine, dopamine and substance P expression in minks[J]. Arch Pharm Res,2009,32(4):565-573.DOI:10.1007/s 12272-009-1413-9.
[12] QIAN Q H, YUE W, CHEN W H, et al. Effect of gingerol on substance P and NK1 receptor expression in a vomiting model of mink[J]. Chin Med J, 2010, 123(4):478-484.
[13]曾建伟,谢勇,林忠宁,等.莲子心抗肿瘤活性部位的筛选研究[J].实用中西医结合临床,2014,14(1):87-88.DOI:10.13638/j.issn. 1671-4040.2014.01.064.
[14]罗光芝,季旭明,马婷,等.基于中医传承辅助平台分析含黄连-干姜药对方剂的组方规律[J].中国药房,2019, 30(1):99-103.LUO G Z, JI X M, MA T, et al. Prescription rules for the prescriptions containing coptis chinensis-zingber ojjicinale couplet medicine based on TCM inheritance support platform[J].China Pharmacy, 2019, 30(1):99-103.
[2] GRUNBERG S, CHUA D, MARU A, et al. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy:randomized, doubleblind study protocol——EASE[J]. J Clin Oncol, 2011, 29(11):1495-1501. DOI:10.1200/JCO.2010.31.7859.
[3]李琳.草酸铈与姜辣素止呕及抗癌增效作用研究[D].青岛:青岛大学,2013.LI L.Cerium oxalate and gingerol anti-nausea effect and anti-tumor effect research[D]. Qingdao:Qingdao University, 2013.
[4]冯霞,易若琨,孙鹏,等.巴莲莲子生物碱提取物对人肝癌细胞HepG2的体外抗癌效果[J].食品科学,2017, 38(19):206-211. DOI:10.7506/spkx1002-6630-201719033.FENG X, YI R K, SUN P, et al. In vitro anticancer activity of alkaloids extracted from ha lotus seeds against human hepatoma HepG2 cells[J]. Food Science, 2017, 38(19):206-211.DOI:10.7506/spkx 1002-6630-201719033.
[5]邵亨元.平安饮治疗妊娠呕吐症[J].新中医,1995, 27(11):37. DOI:10.13457/j.cnki.jncm.1995.11.023.SHAO H Y.Pingan drink for pregnancy and vomiting[J]. NewJournal of Traditional Chinese Medicine, 1995, 27(11):37.DOI:10.13457/j.cnki.jncm. 1995.11.023.
[6]任爱玲,李晓玲,侯宁,等.楷木提取物对小鼠肿瘤的抑制作用[J].徐州医学院学报,2015, 35(10):660-662.
[7]张继国,杨杰,刘占涛,等.一种莲子天然药物组合物及制备方法和抗呕吐用途:CN104138419A[P]. 2014-11-12.
[8]岳旺,张芳,王蕾,等.一种新型呕吐动物模型——水貂[J].药学学报,2003,38(2):89-91. DOI:10.3321/j.issn:0513-4870.2003.02.003.YUE W, ZHANG F, WANG L, et al. A new vomiting animal model-mink[J]. Acta Pharmaceutica Sinica, 2003, 38(2):89-91. DOI:10.3321/j.issn:0513-4870.2003.02.003.
[9]王玉霞,郭兴科,李圆圆,等.高良姜与生姜组合物的抗肿瘤止呕作用[J].泰山医学院学报,2016, 37(7):735-737.DOI:10.3969/j.issn. 1004-7115.2016.07.005.WANG Y X, GUO X K, LI Y Y, et al. The antitumor and antiemetic effect of zingiber and rhizoma composite[J].Journal of Taishan Medical College, 2016, 37(7):735-737. DOI:10.3969/j.issn. 1004-7115.2016.07.005.
[10]杨鹰,王爱民,石振艳,等.紫苏叶与生姜组合物在癌症放、化疗中止吐增效作用[J].中华中医药学刊,2015, 33(2):355-357. DOI:10.13193/j.issn.1673-7717.2015.02.032.YANG Y, WANG A M, SHI Z Y, et al. Detoxification and synergistic effect of zingiber-rhizoma compositionin radiotherapy and chemotherapy[J]. Chinese Archives of Traditional Chinese Medicine, 2015, 33(2):355-357. DOI:10.13193/j.issn. 1673-7717.2015.02.032.
[11] QIAN Q H, YUE W, WANG Y X, et al. Gingerol inhibits cisplatin-induced vomiting by down regulating5-hydroxytryptamine, dopamine and substance P expression in minks[J]. Arch Pharm Res,2009,32(4):565-573.DOI:10.1007/s 12272-009-1413-9.
[12] QIAN Q H, YUE W, CHEN W H, et al. Effect of gingerol on substance P and NK1 receptor expression in a vomiting model of mink[J]. Chin Med J, 2010, 123(4):478-484.
[13]曾建伟,谢勇,林忠宁,等.莲子心抗肿瘤活性部位的筛选研究[J].实用中西医结合临床,2014,14(1):87-88.DOI:10.13638/j.issn. 1671-4040.2014.01.064.
[14]罗光芝,季旭明,马婷,等.基于中医传承辅助平台分析含黄连-干姜药对方剂的组方规律[J].中国药房,2019, 30(1):99-103.LUO G Z, JI X M, MA T, et al. Prescription rules for the prescriptions containing coptis chinensis-zingber ojjicinale couplet medicine based on TCM inheritance support platform[J].China Pharmacy, 2019, 30(1):99-103.